Multi-organ protective effects of ursodeoxycholic acid in a rat model of type 2 diabetes mellitus

This study comprehensively examined the protective effects and underlying mechanisms of ursodeoxycholic acid (UDCA) on multiple organs using a rat model of type 2 diabetes mellitus (T2DM). The findings revealed that UDCA significantly lowered fasting blood glucose levels and ameliorated dyslipidemia by reducing free fatty acids, triglycerides, and total cholesterol. Additionally, UDCA markedly improved hepatic function, as evidenced by decreased levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase, as well as renal function, indicated by reductions in blood urea nitrogen, creatinine, and uric acid. Histopathological evaluations further confirmed that UDCA attenuated pathological damage in the pancreas, liver, and kidneys, preserved islet architecture, and restored the alignment of renal tubules and hepatocytes. Mechanistic investigations demonstrated that UDCA enhanced insulin sensitivity and glucose uptake through activation of the TGR5 receptor, which in turn upregulated downstream AMP-activated protein kinase (AMPK) activity and pancreatic duodenal homeobox-1 (PDX-1) protein expression, while promoting GLUT-4 transcription. Concurrently, UDCA significantly suppressed the secretion of pro-inflammatory mediators, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hs-CRP), mitigated oxidative stress, and inhibited β-cell apoptosis by modulating the expression of Bcl-2 and Bax genes. Collectively, these results indicate that UDCA exerts substantial therapeutic potential in ameliorating metabolic disturbances, repairing organ damage, and regulating critical signaling pathways via multi-target synergistic actions, thereby providing novel experimental evidence supporting its pharmacological application in the treatment of T2DM and its associated complications.